Abstract
Research on human immunology has been hindered by the lack of optimal small animal models, given that the protective immune responses of human and non-human species show significant differences. However, due to ethical constraints[1] and the high cost of clinical trials, it is urgent to improve the current animal models that can mimic faithfully human physiology, particularly the human immune system (HIS). HIS mice had been generated recently by engrafting human hematopoietic stem cells (hHSCs) or human peripheral mononuclear cells (hPBMCs) into highly immuno-deficient mice such as NSG, NOG or NRG mice. However, a major experimental drawback for studies using these models is the rapid onset of Graft-versus-Host Disease (GvHD). In the present study, we overcome this limitation by generating new immuno-deficient mice named "HUMAMICE" (HLA-A2+/+/DR1+/+/H-2-β2m-/-/IAβ-/-/Rag2-/-/IL2rγ-/-/Perf-/- mice), which expressed human HLA molecules instead of mouse MHC molecules (H-2), and whose immuno-deficient status was reversed by transferring functional HLA-matched PBMCs thus producing mice with an immuno-competent status with a functional human immune system. We showed that in this HLA-matched context, the hPBMC-transfer led to high lymphocytes engraftment rates without GvHD over three months in this novel mouse model. Furthermore, to evaluate the utility of the hPBMC-HUMAMICE, we immunized them with commercial vaccine of Hepatitis B virus (HBsAg, Hepvac@) which resulted in robust and reproducible production of high levels of HBsAg-specific antibodies, implying that both transferred T and B lymphocytes were functional in HUMAMICE. These responses are comparable to those observed in human clinical trials with this identical vaccine. In conclusion, these findings indicated that the HLA-matched-hPBMC-HUMAMICE represents a promising model for dissecting human immune responses in various human diseases, including infectious diseases, cancers and tumors, and to facilitate the development of novel vaccines and cellular therapies.
Highlights
Mice functionally engrafted with human hematopoietic cells may represent a valuable preclinical tool for basic and applied investigations of the human immune system[2]
We describe a novel mouse strain derived from the Sure-L1 mouse (HLAA2+/+/DR1+/+/H-2-β2m-/-/IAβ-/-), in which we depleted the murine Rag 2 allele, the interleukin 2 receptor gamma chain allele (IL2rγ) and the perforin allele (Perf), leading to the generation of immuno-deficient mice (HLA-A2+/+/DR1+/+/H-2-β2m-/-/IAβ-/-/Rag2-/-/ IL2rγ-/-/Perf-/- mice) which named HUMAMICE
We show that HUMAMICE developed by backcrossing derived Sure-L1 mice with Rag2-/- mice, IL2rγ-/- mice and Perf-/- mice can be efficiently reconstitute with HLA-matched PBMCs without developing Graft-versus-Host Disease (GvHD) and with a functional immune system able to launch a robust human T cell-dependent response
Summary
Mice functionally engrafted with human hematopoietic cells (hHSCs) may represent a valuable preclinical tool for basic and applied investigations of the human immune system[2]. In contrast to the repopulation of NRG mice with xenogeneic human DQ8-PBMCs which resulted in rapid induction of xeno-GvHD and poor survival rate of the animals, the transfer of HLA-class II-matched human DQ8-PBMCs into NRG IAβ–/–DQ8 transgenic recipients (lacking the expression of murine H-2 class II molecules, and expressing a transgenic HLA-DQ8 molecule) resulted in a milder form of xeno-GvHD, such that the mice survived significantly longer than other previous mouse models These data showed that HLA compatibility between donors and recipients is a requirement for ensuring a proper function of human immune systems in mice without the emergence of graft rejection. The HLA-matched-hPBMC-HUMAMICE model opens the possibility of studying normal human immune-hematopoietic development and human disease pathogenesis for a broad range of biomedical applications
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